Biochemical markers for the prediction of preterm birth

American Journal of Obstetrics and Gynecology

2005 May, S36-46산부인과 조인호

Introduction

Preterm birth is the most responsible for poor pregnancy outcome in the US and many other developed countries.

70% of neonatal death.

½ of preterm birth : long-term neurologic disability

Definition: before 37wks of GA -> spontaneous onset of labor or rupture of the fetal membranes.

Reasons of Prediction of preterm labor

Initiate appropriate risk-specific treatment

Define a population of women who are at risk, -> we can study a particular treatment.

Being able to predict the Preterm labor which ma allow us to gain important insights

Source of biologic fluid

Amniotic fluid, urine, cervical mucus, vaginal secretion, serum or plasma, saliva

Consideration Biologically plausible Ease of collection Costs Safety

Timing

Time that the sample is collected. ALP, ferritine in plasma level

<20wks of gestation : little value in the prediction of a preterm labor

24wks of gestation : highly predictive of preterm birth.

Fetal fibronection >24wks of gestation : less predictive value

Timing

Matrix metalloproteinase-9 24 hours before the Initiation of Labor

or PPROM -> turn positive The time between test turn positive

and the beginning of labor or PPROM is so little.

Timing

Bacterial vaginosis : strong predictor of of prematurity ->sufficiently early in gestational age and intervention.

Fetal fibronectin test : 22-24wks of gestation

The time of day of the sample collection may also be important.

Salivary estriol predicts late preterm births quite well, but 36wks birth is not important.

Predictive value

Any preterm predictive test and positive prdictive values generally should be high for the test to be useful.

Some investigators have found negative predictive value (ie, the ability to predict who will not haver a preterm birth) to be useful and cost saving. Fetal fibronectin : high negative predictive val

ue

Classification of types of biologic marker

Placental proteins A-fetoprotein, major basic protein, placental isoferriti

n Placental protein hormones

CRH, adrenocorticotropin, prolactin, hCG Non-protein hormones

Estrogens, progestines Non-hormonal proteins

ALP, ferritin in placental site or extrauterine sites

Infection-related factors

In the last decade, it has become clear Infection/inflammation has a strong association with preterm delivery.

Define markers of inflammation: C-reative protein : ferritin, interleukins, chemo

kines, cytokines, defensins, bacteria and bacterial products.

y

Cervical and vaginal fluid

Many of substances have been found in cervical or vaginal fluids for their ability to predict spontaneous preterm birth. Gonococcus, Chlamydia, group B- streptococc

us, herpes virus … Baterial vaginosis : 2-fold increased risk o

f spontaneous preterm birth. Associated with an increased risk for intrauter

ine infection.

Cervical and vaginal fluid

Various cytokines associated with preterm birth. IL-6, monocyte chemotactic protein 1, IGF binding prot

ein 1, WBC, collagen synthesis and degradation Fetal fibronectin

Produced by fetal membranes and trophoblasts Before 20wks : not found in the cervix and vagina (>50

ng/mL) 22-24wks : positive 이면 very powerful predictor 24wks : postive 이면 4wks 후 preterm birth 가 올

확률이 60 배 증가

Amniotic fluid

Generally is not obtained from asymptomatic women

GA 16-18wks Increased IL-6

Wenstrom et al : associated with fetal loss within next 4wks Presence of Ureaplasma

Symptomatic women Marker of infection in amniotic fluid

Various cytokines [IL-1, IL-6, TNF-a], WBC, defensins, various metalloproteinases, low glucose levels

Urine

Various hormones and various organisms -> useful marker

Urine DNA examination (Chlamydia, gonorrhea) -> prediction of vaginal or cervical colonization

Saliva

Ultrafiltrate of plasma Easiest fluid to collect Recently, estriol has potential relationship to pre

term labor Unconjugated steroid hormones -> saliva (diffusion)

But, estriol was better marker for late preterm labor

Limitation Patient activity/posture, food consumtion Oral lesions, abrasions, gingivitis

Serum/Plasma

Over the last several decades, hundreds of publications have attempted to evaluate various plasma (or serum) components for predict preterm birth

G-CSF, ferritin level (strongest) High a-fetoprotein, ALP, high CRH (useful mar

ker)

Multiple markers

Powerful predictor A-fetoprotein, ALP, G-CSF (maternal serum) Fetal fibronectin (cervicovaginal mucus) Cervical length (ultrasound)

Several biologic markers together might be useful.

Genomics/Proteomics

Genomics Gene expression -> mRNA Relation

Host genome, gene expression, phenotype

Proteomics Complete protein complement, proteome Relation

Disease, phenotype of interest

Genomics/Proteomics

Genetic study Single nucleotide polymorphism relate on pret

erm birth But, results have been inconsistent Research tools (available)

Gene array chips, gene sequencing Protein array chips, mass spectrometry

Now, these technique has only begun to explored to idendifiy gene/protein

Clinical utility

Identification of biomarkers Insights into the pathophysiologic condition of

these pregnancy complication Identify highest risk women for targeted interv

entions. But, few markers have high test sensitivit

y, specificity, and positive predictive value Few interventions have shown to be of ben

efit to prevent or reduce the incidence of preterm birth

Clinical utility

Scenario Increased cervical/vaginal fetal fibronectin (bi

omarker) -> Antibiotics (intervention) Failed to prevent subsequent preterm birth.

Clinical utility

Recently, Progesterone use to reduce preterm birth. Target : Hx. of preterm birth/not biologic fluid

marker So, define that populaton that is appropriate f

or treatment But, the other various markers haver the pote

ntial to better. In addintion, mid-trimester : maternal serum

progesterone 이 상승 .-> preterm birth 의 marker

Comment

The goal of the study Understand pathways that lead to

preterm birth To define a high-risk population for

future intervention studies To select a population in which a

specific prevention intervention is to be used, or occasionally

To select a population that is at low risk so that they may be spared various interventions.

Comment

Only use of marker for routine prenatal care (single or multiple marker test) -> significant reduction in preterm birth